In 2009, Elizabeth Blackburn received the Nobel Prize in Physiology or Medicine for her work on the biology of so-called telomeres – the DNA sequences found at the end of our chromosomes (actually just a repeating sequence of TTAGGG). The very cool thing about telomeres is that the overall length of these sequences (number of repeating units of TTAGGG) correlates with life-span. This is because as cells in your body are born, they go through a number of cell divisions (each time the cell divides, the telomeres shorten) until they go kaput (replicative senescence). Amazingly, regular cells like these (that normally die after several cell divisions) can be induced to live far longer by simply – lengthening their telomeres (increasing the amount of a telomere lengthening enzyme known as telomerase) – which is why some think of telomeres as the key to cellular immortality.

Imagine your own longevity if all your cells lived twice as long.

With this in mind, it was awesome to read a paper by Dr. Blackburn and colleagues entitled, “Can Meditation Slow Rate of Cellular Aging? Cognitive Stress, Mindfulness, and Telomeres” [doi: 10.1111/j.1749-6632.2009.04414.x]. The authors carefully ponder – but do not definitively assert – a connection between meditative practices and telomere length (and therefore, lifespan). The main thrust of the article is that there are causal links between cellular stress and telomere length AND causal links between physiological stress and meditative practices. Might there, then, be a connection between meditative practices and telomere length?

Given that eastern meditative practices are thousands of years old, its strange to say, but these are early days in beginning to understand HOW – in terms of molecular processes – these practices might influence health.

Still, I think I’ll send some thoughts to my telomeres next meditation session!

The human brain has some 100 billion neurons. That sounds like a lot, but I’m still keen on keeping ALL of mine healthy and in good working order. One way that cells protect themselves from damage and untimely death is by protecting their DNA – by wrapping it up and coiling it tightly – using chromatin proteins – which keeps it away from chemical and viral damage. This is especially important in the brain, since – unlike the skin or gut – we can’t really re-grow brain tissue once its damaged. We have to protect the neurons we have!

Here’s the problem. In order to USE the BRAIN (to learn and remember stuff) we have to also USE the GENOME (to encode the proteins that synapses use in the process of memory formation). When we’re thinking, we have to take our precious DNA out of its protective supercoiled, proteinaceous shell and allow the double helix to melt into single strands and expose their naked A’s, G’s, T’s and C’s to the chemical milieu (to the start the transcription process). This is risky business damage to DNA can lead to cell death!

One might imaging that its best to carry out this precarious act quickly and in proximity to DNA repair enzymes (I’d think). A very important job that includes: uncoiling chromatin superstructures, transcribing DNA (that encodes proteinaceous building blocks that synapses use to strengthen and weaken themselves) – and then – making sure there was no damage incurred along the way. A BIG job that MUST get done each and every time my cells engage in learning. Wow! I didn’t realize that learning new stuff means I’m exposing my DNA to damage? Hmm … I wonder if that PhD was worth it?

To perform this important job, it seems there is an amazing handyman of a molecule named poly(ADP-ribose) polymerase-1 (PARP-1). Amazing, because it – itself – can function in many of the steps involved in uncoiling chromatin structures, transcription initiation and DNA repair. The protein that can “do it all” … get the job done quickly and even fix any errors made along the way! It is known to function in the so-called base excision repair (BER) pathway and is also known have a role in transcription through remodeling of chromatin by ADP-ribosylating histones and relaxing chromatin structure, thus allowing transcription to occur (click here for a great open review of PARP-1). Nice!

According to OMIM, earlier studies by Cohen-Armon et al. (2004) found that poly(ADP-ribose) polymerase-1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because poly(ADP-ribosyl)ation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells (indeed, PARP-1 knock-out mice are more sensitive to DNA damage), it was surprising that activation of the polymerase occurred during learning and was required for long-term memory. Cohen-Armon et al. (2004) suggested that the fast and transient decondensation of chromatin structure by poly(ADP-ribosyl)ation enables the transcription needed to form long-term memory without strand breaks in DNA.

A recent article in Journal of Neuroscience seems to confirm this function – now in the mouse brain. Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation [doi:10.1523/JNEUROSCI.3010-10.2010] by Fontán-Lozano et al., examined cells in the hippocampus at different times during the learning of an object recognition paradigm. They confirm (using a PARP-1 antagonist) that PARP-1 is needed to establish object memory and also that PARP-1 seems to contribute during the paradigm and up to 2 hours after the training session. They suggest that the poly(ADP-ribosyl)ation of histone H1 influences whether H1 is bound or unbound and thus helps regulate the opening and closing of the chromatin so that transcription can take place.

Nice to know that PARP-1 is on the job! Still am wondering if the PhD was worth all the learning. Are there trade-offs at play here? MORE learning vs. LESS something? Perhaps. Check out the paper by Grube and Bürkle (1992)– Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. This gene may influence life span!

Last night I was watching a TV show on the story of The Buddha. There was a part in the story where, “Siddhartha saw a man lying on the ground and moaning. Out of compassion, he rushed over to the man. Channa warned him that the man was sick and that everyone, even noble people like Siddhartha or the king could get sick.” Later, “Siddhartha lost all interest in watching the dancing girls and other such pleasures. He kept on thinking instead about how to free himself and others from sickness, ageing and death.”

When Siddhartha looked at the beautiful young dancers, he saw them as old, dying women and felt empathy for the suffering they would endure in their lives.

This part of the story reminded me of the way mass marketeers often use sexuality to market yoga, and the backlash it creates. I thought that this moment in Siddhartha’s life really captured the “true” spirit of yoga/Buddhism – in stark contrast to so many slick, sexy advertisements. Yoga and meditation – while enjoyed by many young and beautiful people – provides something deeper – a path to cope with the painful, frightening and inexorable loss one’s health, (outer) beauty, memory and breath.

I’d be a hypocrite to say I’m averse to the “sex sells” media, but Siddhartha’s insight is one to keep in mind – and heart.

As far as science movies go, the new movie, “To Age or Not To Age” seems like a lot of fun. The interview with Dr. Leonard Guarente suggests that the sirtuin genes play a starring role in the film. Certainly, an NAD+ dependent histone deacetylase – makes for a sexy movie star – especially when it is able to sense diet and metabolism and establish the overall lifespan of an organism.

One comment in the movie trailer, by Aubrey de Grey, suggests that humans may someday be able to push the physiology of aging to extreme ends. That studies of transgenic mice over-expressing SIRT1 showed physiological properties of calorie-restricted (long lived) mice – even when fed ad libitum – suggests that something similar might be possible in humans.

Pop a pill and live it up at your local Denny’s for the next 100 years? Sounds nice (& a lot like grad school).

Our findings suggest that CR triggers a reduction in Sirt1 activity in hypothalamic neurons governing somatotropic signaling to lower this axis, in contrast with the activation of Sirt1 by CR in many other tissues. Sirt1 may have evolved to positively regulate the somatotropic axis, as it does insulin production in β cells, to control mammalian health span and life span in an overarching way. However, the fact that Sirt1 is a positive regulator of the somatotropic axis may complicate attempts to increase murine life span by whole-body activation of this sirtuin.

To a limited extent, it seems that – in the brain – SIRT1 has the normal function of promoting aging. Therefore, developing “pills” that are activators of SIRT1 would be good for the body, but somehow might be counteracted by what the brain would do. Who’s in charge anyway? Mother Nature will not make it easy to cheat her!Another paper published recently also examined the role of SIRT1 in the brain and found that – normally – SIRT1 enhances neuronal plasticity (by blocking the expression of a micro-RNA miR-134 that binds to the mRNA of, and inhibits the translation of, synaptic plasticity proteins such as CREB).

So, I won’t be first to line up for SIRT1 “activator” pills (such as Resveratrol), but I might pop a few if I’m trying to learn something new.

The concept of “immortality” lies deep in the core of Indian spirituality and the religious traditions of many other cultures. Its probably not a coincidence that one of the first and, still, most influential books on the history of yoga is entitled, Yoga: Immortality and Freedom by Mircea Eliade (you can read the book online here)

Most of the time, this refers to some part of a person – the soul, spirit or otherwise – that lives on forever after the physical body decays. That we are able to recognize and ponder our mortality and the suffering of the physical body, is an integral part of why, in the first place, we seek to practice religion (covered here).

Oxygen is the key to life. This is because it loves electrons. In the mitochondria of every cell in your body, oxygen (in is atmospheric O2 state) serves as the ultimate electron acceptor and provides the chemical energy that drives the formation of ATP (a form of chemical energy storage that our body uses for all its cellular functions).

Oxygen is the key to death. This is because it loves electrons. When so-called reactive oxygen species (small molecules that contain oxygen in an ionized form) are permitted to roam free in cell and the body, they can indiscriminately pull electrons from other molecules (oxidation) and cause undesirable protein damage and premature cell death.

There is no escaping this chemical reality. The very substance that giveth life, doth take it away and our longevity teeters on the quantum mechanical balance of electrons whizzing around the nucleus of the oxygen atom. (I’ll think about this and the chemical symbol for oxygen (O), next time I chant “Om” in yoga class).

So it is with this humbling knowledge that many search for ways to optimize this balance (several populations have already figured out how to routinely live to 100+ years!) or at least improve the quality of our naturally limited life-span. Light exercise, vegetables, friends and not too much alcohol.

Consider the recent paper, by Srivastava et al., “Association of SOD2, a Mitochondrial Antioxidant Enzyme, with Gray Matter Volume Shrinkage in Alcoholics” [doi: 10.1038/npp.2009.217]. The authors report that shrinkage of the neocortex (gray matter) of the brain is associated chronic high levels of alcohol consumption. That’s right, too much alcohol shrinks your brain. Yikes! How does alcohol exert its effect on brain shrinkage? Well, the authors measured many aspects of liver function (various enzyme levels), but these did not correlate with gray matter shrinkage. Rather, the authors traced the effect to an enzyme that normally keeps harmful reactive oxygen species at bay – the so-called superoxide dismutase (SOD) enzyme. We all have this enzyme, but in some of us, those who carry the rs4880 “G” allele of our SOD2 gene produce an enzyme that has an alanine at position 16 (Ala16) and is less active than the rs4880 “A” allele which encodes a more active enzyme with a Valine at position 16 (Val16). The authors report that the rs10370 “TT”, rs4880 “GG” diplo-genotype (diplotype) was associated with more gray matter shrinkage in 76 individuals who report chronic high levels of alcohol consumption. Here, the less active form of SOD2 is seemingly less able to metabolize all the harmful superoxide radicals that are generated during chronic exposure to alcohol. Apparently their neurons are in retreat.

In his undergraduate writings while a student at Harvard in the early 1900’s E. E. Cummings quipped that, “Japanese poetry is different from Western poetry in the same way as silence is different from a voice”. Isabelle Alfandary explores this theme in Cummings’ poetry in her essay, “Voice and Silence in E. E. Cummings’ Poetry“, giving some context to how the poet explored the meanings and consequences of voice and silence. Take for example, his poem “silence”

silence

.is
a
looking

bird:the

turn
ing;edge, of
life

(inquiry before snow

e.e. cummings

Lately, it seems that the brain imaging community is similarly beginning to explore the meanings and consequences of the brain when it speaks (activations whilst performing certain tasks) and when it rests quietly. As Cummings beautifully intuits the profoundness of silence and rest, I suppose he might have been intrigued by just how very much the human brain is doing when we are not speaking, reading, or engaged in a task. Indeed, a community of brain imagers seem to be finding that the brain at rest has quite a lot to say – moreso in people who carry certain forms of genetic variation (related posts here & here).

A paper by Perrson and colleagues “Altered deactivation in individuals with genetic risk for Alzheimer’s disease” [doi:10.1016/j.neuropsychologia.2008.01.026] asked individuals to do something rather ordinary – to pay attention to words – and later to then respond to the meaning of these words (a semantic categorization task). This simple endeavor, which, in many ways uses the very same thought processes as used when reading poetry, turns out to activate regions of the temporal lobe such as the hippocampus and other connected structures such as the posterior cingulate cortex. These brain regions are known to lose function over the course of life in some individuals and underlie their age-related difficulties in remembering names and recalling words, etc. Indeed, some have described Alzheimer’s disease as a tragic descent into a world of silence.

In their recordings of brain activity of subjects (60 healthy participants aged 49-79), the team noticed something extraordinary. They found that there were differences not in how much the brain activates during the task – but rather in how much the brain de-activates – when participants simply stare into a blank screen at a small point of visual fixation. The team reports that individuals who carry at least one copy of epsilon-4 alleles of the APOE gene showed less de-activation of their their brain (in at least 6 regions of the so-called default mode network) compared to individuals who do not carry genetic risk for Alzheimer’s disease. Thus the ability of the brain to rest – or transition in and out of the so-called default mode network – seems impaired in individuals who carry higher genetic risk.

So, I shall embrace the poetic wisdom of E. E. Cummings and focus on the gaps, empty spaces, the vastness around me, the silences, and learn to bring my brain to rest. And in so doing, perhaps avoid an elderly descent into silence.